I. Field of the Invention
This invention relates generally to treatments for cancers and, more specifically, to small molecules that induce cell death and/or suppress cell growth of cancer cells, particularly Ras-mutant and tumorigenic cancer cells.
II. Background
Mutations that lead to activation of three oncogenic ras genes, R-ras, K-ras, and N-ras, were frequently found in a variety of tumor types, including 90% pancreatic, 50% colorectal and 50% lung adenocarcinomas, 50% of thyroid tumors, and 30% myeloid leukemia, but these mutations are not present in normal cells. Of the three ras genes, K-ras mutations are the most frequently found in tumors, including adenocarcinomas of pancreas (70-90%), colon (50%) and lung (50%). Mouse strains carrying alleles of K-ras that can be activated by spontaneous recombination are highly predisposed to a range of tumor types, predominantly early onset lung cancer. Addition of HRAS(V12) or KRAS(V12) mutant gene can be sufficient to render human ovarian surface epithelial cells immortalized with the catalytic subunit of human telomerase reverse transcriptase (hTERT) and the SV40 early genomic region to form tumors in nude mice. Moreover, withdrawal of doxycycline-inducible oncogenic 1H-ras or K-ras can cause apoptosis in tumor cells and regression of tumors of transgenic mice. Therefore, mutations of ras genes play important roles in tumorigenesis and maintenance of malignant phenotypes, and these mutations of ras genes serve as important targets of anticancer therapy. Moreover, because active ras functions are required for replication of some viruses, such as reovirus, hepatitis B virus, herpes virus, and coxsaclievirus and some adenovirus, agents that suppress ras function may also be used as antiviral therapeutics.
Because ras proteins have to be translocated to the inner leaflet of the plasma membrane in order for them to interact with a diversity of membrane receptors and modulate signal transduction of a variety signaling pathways that govern cell growth, proliferation, differentiation and death, agents that interrupt posttranslational modifications required for ras trafficking to the plasma membrane have been intensively investigated for suppression of ras function. For example, farnesyltransferase inhibitors (FTIs) have been intensively investigated in preclinical and clinical cancer therapy. This approach, however, may be effective in preventing the trafficking of H-ras to the plasma membrane, but not K-ras and N-ras, because in the presence of FTIs, N- and K-Ras proteins are geranylgeranylated and transferred to the membrane. Clinical trials from several phase II and phase III studies also showed that FTIs fail to show significant single-agent activity in lung cancer, pancreatic cancer, colorectal cancer, bladder cancer and prostate cancer. Thus, novel compounds that specifically induce cell death or suppress cell proliferation of Ras mutant cells are desirable for anticancer therapy.
A major challenge in cancer therapy is to identify therapeutic agents that are highly specific for malignant cells or malignant tissues. Because malignant cells have the same metabolic pathways as normal cells, and because they are adopted as “self” cells despite the numerous mutations they contain, all anticancer drugs used today affect cellular targets that are shared by normal and cancerous cells. As a result, the use of conventional chemotherapy and radiation therapy is usually limited by a low therapeutic index. In fact, most anticancer drugs used today were discovered because of their ability to kill rapidly dividing cancer cells in vitro and thus are also toxic to rapidly dividing normal cells, such as bone-marrow hematopoietic precursors and gastrointestinal mucosal epithelial cells (Kaelin, 2005). Nevertheless, because of genetic and epigenetic changes in cancer cells, it is possible to identify tumor-selective cytotoxic agents by synthetic lethality screening for compounds that kill cancer cells but not normal cells.